18 / 18
Page 49
O c t o b e r 1 9 - 2 0 , 2 0 1 8 | T o k y o , J a p a n
Pharma Congress 2018 & Molecular Medicine 2018
& Psychiatric Disorders 2018
Asian Journal of Biomedical and Pharmaceutical Sciences
|
ISSN: 2249-622X
|
Volume 8
International Conference on
PHARMACEUTICS AND NOVEL DRUG DELIVERY SYSTEMS
19
th
International Conference on
CELLULAR AND MOLECULAR MEDICINE
19
th
Annual Congress on
PSYCHIATRY AND PSYCHIATRIC DISORDERS
&
&
OF EXCELLENCE
IN INTERNATIONAL
MEETINGS
alliedacademies.comYEARS
Asian J Biomed Pharmaceut Sci 2018, Volume 8 | DOI: 10.4066/2249-622X-C3-009
THE DEVELOPMENT OF
ERBB2
-TARGETED THERAPY FOR ALZHEIMER’S
DISEASE
Yung-Feng Liao, Bo-Jeng Wang, Yun-Wen Chen and Pei-Yi Wu
Institute of Cellular and Organismic Biology, Taiwan
g
-Secretase-catalyzed production of amyloid-b (Ab) underlies the pathogenesis of Alzheimer’s disease (AD). To identify genet-
ic modifiers that can selectively affect g-secretase cleavage of APP while sparing notch cleavage, we generated cell-based
assays employing bioluminescence resonance energy transfer (BRET) technology to monitor the protein-protein interactions
between PS1 and two g-secretase substrates, APP C-terminal fragment (C99), and extracellular domain truncated notch (N∆E).
An RNAi screen examining the effects of lentiviral shRNA clones targeting 777 kinases and 237 phosphatases encoded in the
human genome identified 14 candidate genes whose downregulation resulted in a selective decrease in the interaction between
PS1 and C99. Among those 14 candidate genes, an
ErbB2
-centered interaction network was found to be the most prominent
regulatory signaling network that was predicted to preferentially govern the proteostasis of APP-C99. We further demonstrated
that overexpression of
ErbB2
upregulates the levels of C99 and AICD effectively. The knockdown of
ErbB2
selectively decreased
the protein levels of C99, AICD, and secreted Ab40, but not those of N∆E and NICD. Selective suppression of
ErbB2
expression
by CL-387,785, an ErbB1/2-selective irreversible tyrosine kinase inhibitor, can preferentially attenuate the levels of C99 and AICD,
resulting in a significant reduction in Ab production. Down-regulation of
ErbB2
by CL-387,785 also resulted in a significant de-
crease in the levels of C99 and secreted Aβ in both zebrafish and mouse models of AD, through the activation of autophagy. Oral
administration of CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice.
These findings unveil a noncanonical function of
ErbB2
in modulating autophagy and establishe
ErbB2
as a novel therapeutic
target for AD.